Patent EA-000719-B1 (EA)
Title: Farnesyl transferase inhibiting 2-quinolone derivatives
Inventor: END DAVID WILLIAM
IPC: A61K31/47
Filed: 1996-10-25
Abstract: 1. A compound of formula (I)   a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof; wherein the dotted line represents an optional bond; X is oxygen or sulfur; R<1> is hydrogen, C1-12 alkyl, Ar<1>, Ar<2> C1-6 alkyl, quinolinyl C1-6 alkyl, pyridyl C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, mono- or di(C1-6 alkyl)amino C1-6 alkyl, amino C1-6 alkyl, or a radical of formula -Alk<1>-C(=O)-R<9>, -Alk<1>-S(O)-R<9> or -Alk<1>-S(O)2-R<9>, wherein Alk<1> is C1-6 alkanediyl, R<9> is hydroxy, C1-6 alkyl, C1-6 alkyloxy, amino, C1-8 alkylamino or C1-8 alkylamino substituted with C1-6 alkyloxycarbonyl; R<2> and R<3> each independently are hydrogen, hydroxy, halo, cyano, C1-6 alkyl, C1-6 alkyloxy, hydroxy C1-6 alkyloxy, C1-6 alkyloxy C1-6 alkyloxy, amino C1-6 alkyloxy, mono- or di(C1-6 alkyl) amino C1-6 alkyloxy, Ar<1>, Ar<2> C1-6 alkyl, Ar<2> oxy, Ar<2> C1-6 alkyloxy, hydroxycarbonyl, C1-6 alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6 alkenyl; or when on adjacent positions R<2> and R<3> taken together may form a bivalent radical of formula -O-CH2-O-   (a-1), -O-CH2-CH2-O-   (a-2), -O-CH=CH-   (a-3), -O-CH2-CH2-   (a-4), -O-CH2-CH2-CH2-   (a-5), or -CH=CH-CH=CH-   (a-6); R<4> and R<5> each independently are hydrogen, Ar<1>, C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, amino, hydroxycarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkyl S(O) C1-6 alkyl or C1-6 alkyl S(O)2 C1-6 alkyl; R<6> and R<7> each independently are hydrogen, halo, cyano, C1-6 alkyl, C1-6 alkyloxy orAr<2> oxy; R<8> is hydrogen, C1-6 alkyl, cyano, hydroxycarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkylcarbonyl C1-6 alkyl, cyano C1-6 alkyl, C1-6 alkyloxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyl, hydroxy C1-6 alkyl, amino C1-6 alkyl, mono- or di(C1-6 alkyl) amino C1-6 alkyl, halo C1-6 alkyl, C1-6 alkyloxy C1-6 alkyl, aminocarbonyl C1-6 alkyl, Ar<1>, Ar<2> C1-6-alkyloxy C1-6 alkyl, C1-6 alkylthio C1-6 alkyl; R<10> is hydrogen, C1-6 alkyl, C1-6 alkyloxy or halo; R<11> is hydrogen or C1-6 alkyl; Ar<1> is phenyl or phenyl substituted with C1-6 alkyl, hydroxy, amino, C1-6 alkyloxy or halo; and Ar<2> is phenyl or phenyl substituted with C1-6 alkyl, hydroxy, amino, C1-6 alkyloxy or halo. 2. A compound as claimed in claim 1 wherein X is oxygen. 3. A compound as claimed in claim 1 wherein R<1> is hydrogen, C1-6 alkyl or C1-6 alkyloxy C1-6 alkyl. 4. A compound as claimed in claim 1 wherein R<6> is hydrogen and R<7> is halo. 5. A compound as claimed in claim 1 wherein R<8> is hydrogen, C1-6 alkyl or hydroxy- C1-6 alkyl. 6. A compound as claimed in claim 1 wherein the compound is. 4-(3-chlorophenyl)-6-[(4-chlorophenyl)-lH-imidazol-l-ylmethyl]-l-methyl-2(1H)-quinolinone; 4-(3-chlorophcnyl)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-2(lH)-quinolinone; 6-[1-(4-chlorophenyl)-2-hydroxy-1-(1H-imidazol-1-yl)ethyl]-1-methyl-4-phenyl-2(1H)-quinolinone; 4-(3-chlorophenyl)-6-[1-(4-chlorophenyl)-1H-imidazol-1-yl)ethyl]-1-methyl-2(1H)-quinolinone; 4-(3-chlorophenyl)-6-[ 1 -(4-chlorophenyl)-1-(5-methyl-1H-imidazol-1-yl)ethyl]-l-methyl-2(1H)-quinolinone; 4-(3-chlorophenyl)-6-(1-(4-chlorophenyl)-2-hydroxy-1-(1H-imidazol-1-yl)ethyl]-l-methyl-2(1H)-quinolinone; 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(IH-imidazol-l-yl)methyl]-l-(2-methoxyethyl)-2(lH)-quinolinone ethanedioate (2:3) monohydrate; 6-[(4-chlorophenyl)(lH-imidazol-l-yl)methyl]-4-(l,3-benzodioxol-5-yl)-l-methyl-2(lH)-quinolinone ethanedioated (1:1); a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salts thereof. 7. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 to 6. 8. A process of preparing a pharmaceutical composition as claimed in claim 7 wherein the pharmaceutically acceptable carriers and a compound as claimed in claim 1 to 6 are intimately mixed. 9. A compound of formula (XVI) wherein the radicals R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<10> and R<11> are as defined in claim 1, or a pharmaceutically acceptable add addition salt thereof.   10. A compound of formula (XV) wherein the radicals R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<10> and R<11> are as defined claim 1, or a pharmaceutically acceptable acid addition salt thereof.   11. A compound as claimed in any of claims 1 to 6 for use as a medicine. 12. A process for preparing a compound as claimed in claim 1, characterized by N-alkylating an imidazole of formula (II) or an alkali metal salt thereof with a derivative of formula (III);   or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof. 13. A process for preparing a compound as claimed in claim 1, characterized by reacting an intermediate of formula (IV) with a reagent of formula (V), wherein Y is either carbon or sulfur, such as, for example, a 1,1'-carbonyl-bis[1H-imidazole]   or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof. 14. A process for preparing a compound as claimed in claim 1, characterized by cyclizing an intermediate of formula (VI) thus obtaining compounds of formula (I-a), defined as a compound of formula (I) wherein the dotted line is a bond, may also be obtained   or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof. 15. A process for preparing a compound as claimed in claim 1, characterized by hydrolysing an intermediate of formula (XXVI), wherein R is C1-6 alkyl, in an aqueous acid solution, yielding a compound of formula (I-a-1) defined as a compound of formula (I-a) wherein R<1> is hydrogen   or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof. 16. A process for preparing a compound as claimed in claim 1, characterized by opening an epoxide of formula (VII) with an imidazole of formula (II) thus obtaining a compound of formula (I-b), defined as a compound of formula (I) wherein R<8> is hydroxymethylene   or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof. 17. A process for preparing a compound as claimed in claim 1, characterized by transforming intermediate nitrones of formula (XV), prepared by N-oxidizing quinoline derivatives of formula (XVI), either by csterfonnation and subsequent hydrolysis or via a intramolecular photochemical rearrangement, thus yielding compounds of formula (I-f-1)   or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof.